Osteoporosis and sarcopenia are major clinical problems in the aging population and in many patients these two conditions occur concurrently. This combination results in instability, susceptibility to falls and consequently to fracture, morbidity, and premature death. It is unclear whether one condition precedes the other or if the conditions are linked. The traditional view of skeletal muscle and bone interaction is that skeleta muscle loads bone and bone provides an attachment site for muscle. The mechanical perspective implies that as muscle function declines, this would result in decreased loading of the skeleton and therefore would result in a decrease in bone mass. However, muscle atrophy alone cannot fully explain the totality of osteoporosis and, reciprocally, aging associated decreases in bone mass do not fully explain sarcopenia. Our preliminary data suggest that soluble factors may play a role in crosstalk between bone and muscle. The hypothesis for the Program Project is that there is an endocrine loop between muscle and bone through the production of systemic factors by each tissue that are critical regulatory factors for function in the other tissue. The osteocyte response to mechanical loading by the action of muscles is modified by these muscle secreted factors. In turn, the osteocyte regulates both osteoblast and muscle cell function through modulators of the Wnt/beta-catenin pathway. A series of experiments to examine the role of the osteocyte in muscle-bone crosstalk and what happens with aging are proposed. The specific aims are 1). Determine the effects of muscle on osteoblast/osteocyte function with aging, 2). Determine the effects of osteocytes on muscle mass and function with aging, 3). Examine osteocyte regulation of osteoblast function with aging and how this is regulated or influenced by muscle-bone crosstalk, and 4). Determine the effects of mechanical loading on osteocyte regulation of muscle mass and function with aging. This program project is innovative in concept, preliminary data, approach, tools, interdisciplinarity, and cadre of investigators. The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia.